title: Population pharmacokinetics meta-analysis of plitidepsin (Aplidin) in cancer subjects.
abstract: OBJECTIVE
  To characterize the population pharmacokinetics of plitidepsin (Aplidin) in cancer patients.
  
  
  METHODS
  A total of 283 patients (552 cycles) receiving intravenous plitidepsin as monotherapy at doses ranging from 0.13 to 8.0 mg/m(2) and given as 1- or 24-h infusions every week; 3- or 24-h infusion biweekly; or 1-h infusion daily for 5 consecutive days every 21 days were included in the analysis. An open three-compartment pharmacokinetic model and a nonlinear binding to red blood cells model were used to describe the plitidepsin pharmacokinetics in plasma and blood, respectively, using NONMEM V software. The effect of selected covariates on plitidepsin pharmacokinetics was investigated. Model evaluation was performed using goodness-of-fit plots, posterior predictive check and bootstrap.
  
  
  RESULTS
  Plasma clearance and its between subject variability (%) was 13.6 l/h (71). Volume of distribution at steady-state was calculated to be 4791 l (59). The parameters B (max) and C (50) of the non-linear blood distribution were 471 microg/l (56) and 41.6 microg/l, respectively. Within the range of covariates studied, age, sex, body size variables, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin, creatinine clearance, albumin, total protein, performance status, co-administration of inhibitors or inducers of CYP3A4 and presence of liver metastases were not statistically related to plitidepsin pharmacokinetic parameters. Bootstrap and posterior predictive check evidenced the model was deemed appropriate to describe the time course of plitidepsin blood and plasma concentrations in cancer patients.
  
  
  CONCLUSIONS
  The integration of phase I/II pharmacokinetic data demonstrated plitidepsin linear elimination from plasma, dose-proportionality up to 8.0 mg/m(2), and time-independent pharmacokinetics. The distribution to red blood cells can be considered linear at doses lower than 5 mg/m(2) administered as 3-h or longer infusion. No clinically relevant covariates were identified as predictors of plitidepsin pharmacokinetics.
authors.affiliation: Department of Engineering, Pharmacy and Pharmaceutics Division, Faculty of Pharmacy, Miguel Hernández University, San Juan de Alicante, Alicante, Spain. jnalda@umh.es
authors.forename: Ricardo
authors.initials: R
authors.lastname: Nalda-Molina
authors.forename: Belén
authors.initials: B
authors.lastname: Valenzuela
authors.forename: Amelia
authors.initials: A
authors.lastname: Ramon-Lopez
authors.forename: Bernardo
authors.initials: B
authors.lastname: Miguel-Lillo
authors.forename: Arturo
authors.initials: A
authors.lastname: Soto-Matos
authors.forename: Juan Jose
authors.initials: JJ
authors.lastname: Perez-Ruixo
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects / Q000378:metabolism; D047630:Depsipeptides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy*; D017711:Nonlinear Dynamics; D010456:Peptides, Cyclic; D013997:Time Factors; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D047630:Depsipeptides; D010456:Peptides, Cyclic; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C098980:plitidepsin